The central theme of this Program Project is that the dimensions of the pain experience (e.g., pain intensity, localization, and persistence) can far exceed those expected on the basis of peripheral tissue injury or pathology whenever CNS regulatory systems are dysfunctional. Up to now, a lack of methods for the direct evaluation and characterization of the status of these systems has deterred progress in understanding CNS pain regulatory mechanisms. To address this gap, state-of-the-art human psychophysical and neuroimaging methods (combined quantitative EEG and fMRI) will be used to evaluate, at the level of the cerebral cortex, the status of CNS pain and touch regulatory mechanisms in patients diagnosed with fibromyalgia syndrome (FM) and with myogenous temporomandibular dysfunction (TMD), and in normal healthy subjects. Psychophysical findings have suggested abnormalities in three such processes that will be targeted by the proposed psychophysical and neuroimaging experiments: diffuse noxious inhibitory control (DNIC, inhibition of pain by pain), the touch gate (inhibition of mechanoreception by pain), and the pain gate (inhibition of pain by mechanoreception). In addition, longitudinal epidemiological approaches will be used to determine whether abnormalities in CNS regulatory systems predict the subsequent development of TMD in otherwise healthy young adult females. The primary hypothesis that guides this work is that dysfunction(s) within CNS regulatory systems increases pain sensitivity and represents an important risk factor that contributes to the development of central sensitization which leads to persistent musculoskeletal pain conditions like myogenous TMD. The long-term goals of this Program Project are to: 1) To obtain experimental evidence enabling mechanistic interpretation and quantification of the physiological/biological processes that mediate the intense, abnormally widespread, and persistent pain exhibited by patients with disorders of central sensitization. 2) To develop and validate novel psychophysiological and neurophysiological approaches that permit quantitative assessment of the peripheral and CNS pathophysiology associated with disorders of central sensitization and pain regulation. 3) To establish an environment that enables effective and productive interactions between basic scientists and clinicians interested in central pain and its regulation. 4) To generate a research environment that facilitates translation of basic science findings into therapeutic interventions for the treatment of persistent musculoskeletal pain.